Key players in the global response to the outbreak of severe acute
respiratory syndrome (SARS) jammed the Natcher auditorium May
30 as NIAID  NIH's lead component in addressing the
emerging infectious disease  hosted an international
research colloquium on "SARS: Developing a Research Response."
Authorities from government, academia, public health and industry
joined for a daylong workshop; the morning was devoted to plenary
sessions defining the scope of the problem, while afternoon sessions
addressed specific strategies in vaccine and antiviral development, as
well as clinical research and epidemiology.

Continued...

HHS Secretary Tommy Thompson, appearing by live video,
launched the meeting with praise for the scientific community's
"rapid, skillful and amazingly successful start so far" in containing
and characterizing SARS, and noted that the SARS challenge "is big
enough to keep all of us busy for a very long time...The hopes and
prayers of many people around the world are with you today."

NIAID director Dr. Anthony Fauci cautioned that the session "is
certainly not the last meeting we'll have on this very important
disease," then displayed a slide he has shown for years depicting
emerging and reemerging diseases around the globe. "This slide
requires almost continual updating," he said. "Some (of the diseases)
are merely curiosities, others have great public health impact both in
their reality and potential." As of May 28, he said, there had been
8,240 reported cases of SARS, with 745 deaths, most of them in the
Far East. Addressing SARS "will require many partners...all of us
working in synergy," Fauci said.

Dr. Klaus Stöhr of the WHO addresses meeting.

Describing SARS epidemiology was Dr. Klaus Stöhr, project leader
of the World Health Organization's global influenza programme. In
spite of signs that the SARS outbreak was declining at the end of
May, Stöhr warned, "Complacency can lead to the reemergence of
this disease."

He said the outbreak began in the last quarter of 2002. Health care
workers were at greatest risk of contracting SARS in the early stages
of the outbreak. The illness appears to have a 15 percent fatality
rate, but he cautioned the sample size has been small. Almost
three-quarters of SARS deaths occur in people over age 60. "Age is
definitely a risk factor, as is comorbidity," he said. "Males are
slightly more at risk than females, but again, the sample size is
small."

His slides were fact-laden and his presentation rigorous: A person is
most infectious in the first 7 days after acquiring the disease; it is not
known if the route of infection (direct mucous membrane contact,
fecal/oral contact) influences the incubation period; there is no
evidence of SARS transmission before the onset of first symptoms;
the people most ill are also the most infectious to others; there is no
evidence of food- or water-borne SARS; there has been no
transmission on an airliner since Mar. 23; seroconversion can occur
in the absence of disease; children seem to have a built-in defense
against the virus, getting only mildly ill in most cases.

A veterinarian by training, Stöhr is exploring whether masked palm
civets, raccoon dogs and other animals found in Chinese food
markets are reservoirs for SARS.

Dr. Malik Peiris

Explaining SARS etiology was Dr. Malik Peiris, professor in the
department of microbiology at the University of Hong Kong, which
helped identify a new coronavirus as the cause of SARS. He said
that people in the United States who have not traveled to Asia
recently "can't have a feel for how devastating in social and
economic terms SARS is."

He recounted early reports last February of an outbreak of atypical
pneumonia in Guangdong province in China, and said it was quickly
appreciated that something other than influenza or other
conventional respiratory virus was at work. Scientists soon learned
that the SARS coronavirus was more stable in the environment than
other respiratory viruses, and could survive for as long as a few
days on dry surfaces at room temperature, Peiris reported.

"For the front-line health care workers, it was basically fighting a
war," he said, to a spontaneous wave of applause.

Offering a view from the trenches was Dr. Allison McGeer, director
of infection control at Mt. Sinai Hospital in Toronto, who expressed
both her gratitude for a "phenomenal degree of collaboration and
willingness to help" on the part of the international public health
community, and her pleasure at finally being able to spend a day
without wearing a mask.

Dr. Allison McGeer

"Hospitals are the epicenter of this outbreak," she reported; patients,
visitors and health care workers are at highest risk of infection. The
venues next most susceptible to SARS transmission are doctors'
offices, households and family members of SARS patients. The
virus rarely pops up in the community outside these sites, she said,
and only one instance of workplace (other than hospital)
transmission has been reported in Toronto.

She related a fearsome tale of a SARS patient who arrived at a
Toronto hospital by ambulance with his wife, who did not yet
realize she was infected. In mere hours in the ER and adjoining
rooms, the pair infected almost everyone in the vicinity, even
housekeepers, visitors and passersby. Commented Fauci, "It's
astounding that we have only 8,000 cases, and not 80,000 or
800,000 cases, given this level of infectivity."

McGeer said that abnormal chest X-rays don't show up in SARS
patients until around day 7 of illness. "This is a slowly progressive
disease," she emphasized. Severity peaks at days 13-17, and in
cases that proceed to mortality, the process lasts around 7 weeks,
she said.

An impressive amount of scholarship already has been devoted to
coronaviruses, as evidenced in talks given by Dr. Kathryn Holmes
of the University of Colorado and Dr. Mark Denison of Vanderbilt
University Medical Center, both long-time NIH grantees. "A very
large international group has been studying coronaviruses in animals
and man," Holmes said. The coronavirus group was first recognized,
by electron microscopy, in the late 1960's, she said. The spikes that
characterize the surface of the round viral particles are viral fusion
proteins, and are specific to certain tissues, she added. "Fifteen to 30
percent of colds in people are due to one of the coronaviruses," she
reported. The SARS-CoV has a 30,000-base RNA genome, which
Denison dubbed "the genome from hell."

Dr. Yuming Shao comments from the audience.

Coronaviruses fall into three distinct genetic groups, Holmes said;
the SARS-CoV may belong to a new, fourth group. It appears to
favor the lower respiratory tract in humans, and almost never the
upper, and Holmes believes it can be enteric as well, mimicking the
dual respiratory-enteric sites of other coronavirus infection in
animals. She is optimistic that the SARS virus offers "many potential
targets for drugs, including blocking and inhibition of various
receptor interactions."

The morning session concluded with a rousing endorsement of the
NIH model of funding basic research on the faith that it will reap
benefits downstream. Vanderbilt's Denison, who described himself
comically as "just a little old country virologist from Tennessee,"
applauded the value of basic research, which prompted another
ovation from the audience. "I've been funded for 18 years by NIH,"
he said, "and I can tell you that the NIH investment in coronavirus
biology in the past 20 years is less than the daily cost of the SARS
epidemic worldwide."

He said the SARS outbreak "scares me  it has incredible
pandemic potential." He said the health care workers who have
responded to the epidemic "are my heroes," and cautioned that the
outbreak could have been much worse. Glad for the newfound
attention to his field, Denison reported that "there have been more
coronaviruses sequenced in the past month than in the past 25
years."

The afternoon of the colloquium was devoted to breakout sessions
designed to give NIAID what Secretary Thompson hoped at the
outset would be "an aggressive set of goals" for containing and
managing this new disease.

The day before his institute hosted a major international meeting on
SARS, NIAID director Dr. Anthony Fauci answered some questions
about NIH's response to severe acute respiratory syndrome, an
emerging viral illness that in some respects mirrors the emergence of
AIDS more than two decades ago.

When did you first become aware of the epidemic and what were
the first steps?

It was right around the end of February, the beginning of March.
We had heard of these cases in Hong Kong, and there was an
interesting series of events that had occurred in late 2002, when we
were hearing rumors that there was some atypical type of
pneumonia in China. And we were not sure whether it was a repeat
of the H5N1 flu that jumped species from birds to human. We were
a little concerned because we were afraid that there might be an
H3N2 flu circulating in China. When you have somebody coinfected
with H5N1 and H3N2, then you could wind up having a situation
where the bird flu can be easily transmitted from human to human.
Because when the two combine, they could assume the capabilities
of not only jumping from a fowl to a human, which is H5N1, but
(also) the naturally human infection, H3N2, can be combined in the
same person. So we were thinking that maybe something was going
on in China that was very vague  the reports were not very
robust  it was just 'Something funny is going on in China.'

At the end of February, beginning of March, when the cases of
something that clearly was not flu were going on in Hong
Kong  and the reason we know is that the people in Hong
Kong know what they are doing; they are very sophisticated, they
know how to diagnose flu  and they were saying, 'We're
having a strange cluster of cases where we do not know what it is,
but it seems to be spreading from person to person, we do not have
an etiologic agent, it appears to be respiratory-borne, and it is very
high-risk among health workers taking care of the patients.'

We had in Geneva one of our own NIAID people  Lone
Simonsen  gathering information. She was there for another
reason, (but) we told her to stay there and see what she could find
out, at the same time that the CDC was trying to make contacts in
Hong Kong as well as in China, if possible. It was at that point when
I spoke to her and others on the phone that this was a serious issue.
So then we said, 'Wait a minute  this we have to take very
seriously.' And then everything exploded [in the world media].

When it became clear that we were dealing with a new disease, the
agent (of which) we did not know, we immediately gathered our
forces at NIAID and said, 'This is another emerging disease, we've
got to prepare for it, we've got to get our people ready to move as
quickly as possible.' So as soon as the agent was identified as a
coronavirus, then it became very clear that we had the opportunity
to do drug screening and to grow the virus in culture. We started a
vaccine endeavor with both intramural and extramural (scientists)
and we began talking to industry about the possibility of getting
drugs for them to put into our screening capability. We already have
a contract that is a collaboration with CDC, USAMRIID (U.S.
Army Medical Research Institute of Infectious Diseases), and
NIAID  and it is a drug-screening contract, so we
immediately plugged that in and started looking at the effect of
certain already well-known antivirals, as well as some compounds
that have not been fully developed. We started the screening
process. Brian Murphy of our intramural Laboratory of Infectious
Diseases got the virus from the CDC and began growing it in his lab
for the purpose of developing a vaccine. Gary Nabel in NIAID's
Vaccine Research Center got the sequences from the CDC, so
began doing the molecular approach with his vector
approach  he has been working with adenovirus vector with
the company GenVec. He has been making an HIV vaccine using an
adenovirus vector; he immediately adapted that to the SARS [virus]
and is now working with that. Subsequently, we began sending out
the word to our grantees, particularly those who have been funded
on coronavirus over the years  not the SARS coronavirus,
but coronavirus in general  getting them interested in using
their expertise to start thinking and talking about the coronavirus
that's causing SARS...We put together a first-stage research agenda
involving basic research, pathogenesis, antiviral screening, targeted
antiviral, vaccines, animal model development, and then a clinical
component, and that was what you read about and heard about with
the Clinical Center being involved. We felt we had the responsibility,
if it came to that, to study SARS-infected people in the Clinical
Center. As it turns out we don't have a lot of cases [in the U.S.], so
the worry about that, which I think was understandable, [did not
materialize]. We were very concerned about safety. So we are
looking at not only studying acutely infected people  which
there are not very many around in this country, in fact there are
none right now  but also how long people shed virus. What
about people in the convalescent stage? If we bring people in who
have been infected, [we want to] look at their immunological
response, to see if there is any residual evidence of virus. If they are
asymptomatic, does the asymptomatic state coincide with a good
immunological response? So there are a whole host of questions that
are involved.

Is there still a possibility that the Clinical Center will admit SARS
patients?

Yes. Oh, absolutely.

Are there such things as "superspreaders" in other infectious
diseases or is this a novelty?

Superspreaders is somewhat of a misleading term. There is a
biological variability; there are people who, for a variety of reasons,
shed more virus, or shed virus when they are asymptomatic, which
gives them a greater opportunity to come in contact with other
people and spread it more readily versus a person who is very sick
and would only have contact with close family members or hospital
people. So the idea about a superspreader is not a new concept.
There are people with HIV infection who are very efficient
transmitters of HIV, for a number of reasons  they may
have genital ulcers that allow the virus to be shed more readily in
their genital tract, they may have a high titer of virus that easily spills
over into seminal fluid or vaginal secretions  so the answer
to your question is that it is not unheard of...The typical distribution
curve of efficiency of transmission is very common in different
diseases.

NIAID director Dr. Anthony Fauci visits with Dr. Kathryn
Holmes, a virologist at the University of Colorado who has studied
coronaviruses for many years.

How similar is the emergence of SARS to AIDS in your personal
experience?

It's different because HIV/AIDS is a behaviorally spread disease.
SARS is a respiratory disease and hence everyone could be at risk,
so there is a big, big difference in how it is spread. The similarities
are that A) It is a brand new disease, B) It is a newly recognized
virus that belongs to a class of viruses that has been known. [AIDS]
was a retrovirus; we knew about retroviruses but we did not know
about AIDS. This is a coronavirus; we knew about coronaviruses,
but we did not know about SARS. It is brand new, it causes a
serious disease, it could be fatal, and it very likely jumped from an
animal species to a human, so it is what we call a zoonotic infection.
The primary animal reservoir(s) of SARS are currently unknown;
with AIDS, the chimpanzee likely was the main source of HIV-1
and the monkey the main source of HIV-2.

Are other NIH institutes and centers involved in SARS research?

Right now, I do not know of any others that are involved...There
may be...but there's no major involvement other than NIAID.

How likely is it that the current outbreak is a "herald wave" or
harbinger of worse things to come next fall?

We don't know, and that's the big unknown, and that's the reason
why we have to be very vigilant and take this extremely seriously,
because we are still in the evolutionary stage of an epidemic. We do
not know whether it is going to plateau a little bit, then take off
again, or whether it is going to drop dramatically and then come
back in a seasonal way. We just do not know.

Is it surprising to you that there has been a reemergence of SARS
in Toronto (as of late May)?

Not at all. I've been saying that before congressional committees. It
ain't over 'til it's over. You've really got to be careful; there could be
undetected chains of transmission that might pop up again, and
that's exactly what happened in Canada.